Regulation of cell proliferation and differentiation in the kidney

Abstract

The mammalian cut proteins are a broadly expressed family of nuclear transcription factors related to the Drosophila protein cut. One member of the cut family, Cux1, has been shown to function as a cell cycle dependent transcription factor, regulating the expression of a number of cell cycle regulatory proteins. Cux1 expression is developmentally regulated in multiple tissues suggesting an important regulatory function. Cux1 exists as multiple isoforms that arise from proteolytic processing of a 200 kD protein or use of an alternate promoter. Several mouse models of Cux1 have been generated that suggest important roles for this gene in cell cycle regulation during hair growth, lung development and maturation, and genitourinary tract development. Moreover, the aberrant expression of Cux1 may contribute to diseases such as polycystic kidney disease and cancer. In this review, we will focus on the phenotypes observed in the five existing transgenic mouse models of Cux1, and discuss the role of Cux1 in kidney development and disease.

Figure 1

The Cut superclass family of homeodomain proteins. The Cut superclass homeodomain transcription factor family tree consists of the ONECUT family members, the SATB family members, the CUX family members, and the CMP family members. Motifs include cut repeats (CR), homeodomain (HD) and Compass domain (COMP).

Figure 2

Structure of the Cux1 homeodomain proteins. The full-length Cux1 protein (p200) contains three cut repeat domains and the cut homeodomain. The testis specific Cux1 (p55) contains one cut repeat and the cut homeodomain (37). p75, contains one cut repeat and the cut homeodomain and is produced from an alternate promoter (38). p90, and p110 contain two cut repeats and the cut homeodomain and are products of proteolytic processing of p200 by a nuclear isoform of Cathepsin-L (41, 44). p150 is a product of C-terminal proteolytic processing within the homeodomain during mammary gland differentiation (42). p80 is a product of C-terminal proteolytic processing of p110 by a caspase (43).

Figure 3

Murine models for Cux1. There have been five genetically engineered mouse models for Cux1. The structure of the resulting Cux1 protein, as it exists within each mouse model, is represented next to the observed phenotype.

Figure 4

Cux1 regulation of p27 during kidney development. Cux1 is highly expressed in the early stages of nephrogenesis, where expression is associated with cell proliferation and repression of p27. At later stages of nephrogenesis, Cux1 is down regulated, which is permissive for p27 to be expressed resulting in cell cycle arrest and terminal differentiation.